1. Field of the Invention
The present invention relates to a double chamber container which is suitable, in particular, for lyophilization, to a process for filling the double chamber container, to a process for mixing the two components contained in the double chamber container, and to the use of the container.
2. Description of the Prior Art
There are pharmaceutical compositions which in their liquid state very rapidly lose their efficacy. To enable these compositions to be used in spite of their short shelf life, specific devices and processes for lyophilization have been developed. Thus, pharmaceutical preparations which cannot be used in solution over relatively long periods may be made durable by lyophilization and possibly stored away from air. The dry substance is only dissolved again, i.e., reconstituted, immediately before use. For this purpose, two-component systems have become known for re-dissolving the lyophilizate immediately before use.
As is known, lyophilizates are also used in ready-prepared syringes with two-chamber systems—the lyophilizate and solvent being stored separately and only combined just before use. Two-chamber prepared syringes of this kind have already been described in “Die Lyophilizierung von Arzneimitteln in Fertigspritzen”, H. Vetter, Die Pharmazeutische Industrie, Vol. 46, 1984, No. 10, pp. 1045-1049. Specifically, ready-prepared syringes of this kind are constructed so that each of the components is housed in its own chamber, the chambers being arranged axially behind one another and only brought into contact with one another immediately before use, so that the liquid component in one chamber can flow over to the dry component in the other chamber.
In the prior art attempts have been made to find further solutions to carry out, using double chamber systems of this type, lyophilization of the solid substance present in solution, which substance may then, or after appropriate storage prior to application, be re-dissolved, the sterility of the two components being maintained during mixing. The lyophilization of solutions in a syringe is possible only under specific conditions, the fact that during the lyophilization there is only a very small cross section for the exchange of gases being problematic. The prior art contains numerous proposals to solve these problems:
Known, for example, is a multi-chamber disposable syringe according to DE 33 11 525, in which the lyophilizate is present in the syringe cylinder, in particular in the first syringe chamber which is connected to the syringe neck and is separated from the second syringe chamber by the syringe plunger. The freeze-drying, which is designed in particular for a container having a narrow opening, is carried out via two openings, for example by means of a hollow needle which is guided through the syringe neck into the first syringe chamber and is connected to an ice condenser and a vacuum pump, a second opening, through which dried gas is introduced, being provided by the free annular space between the hollow needle and syringe neck. Two hollow needles may also be pierced through the resilient plunger body from the trailing end of the syringe cylinder in order thus to freeze-dry the liquid product in the first cylinder chamber.
The patents and patent applications described in the following paragraphs, namely U.S. Pat. No. 5,788,670, EP 0 718 002 A2, U.S. Pat. No. 4,254,768, and EP 0 295 337 B1 are incorporated herein by reference in their entireties.
U.S. Pat. No. 5,788,670 describes a double chamber syringe which may be broken down into two parts, wherein two medical components may be respectively introduced into the separate cylinders and the medicament in the lower cylinder part subjected to lyophilization, both cylinder parts then being sealed and interconnected.
Similarly, EP 0 718 002 A2 describes a two-chamber syringe having a syringe cylinder consisting of two partial cylinders. For the purposes of lyophilization, the syringe head may be provided with a closure cap having axially extending recesses which provide a connection to the environment when the cap is not completely attached. The lyophilization takes place in one partial cylinder. The weak point of a construction of this type is the connection between the two chambers which, in the event of insufficient tightness, not only provides a possible point for contamination but may also result in leakage of the liquid substance during mixing. An additional process step, which must satisfy extremely stringent requirements, for connecting both partial cylinders is required. The closure cap has the further drawback that precise adjustment must be carried out to allow the recesses in the closure cap to be outwardly connected; this is not easily possible, since the recesses are concealed by the cap, owing to the shape thereof, so the position of the recesses is not easy to establish. Connection to a recess of this type—such as may, for example, prove advantageous during the lyophilization—is also not possible. In addition, the closure must be adapted to the specific shape of a syringe head.
According to U.S. Pat. No. 4,254,768, a double chamber syringe also consists of two separate cylinders which may be joined. A vent, which may be re-closed by pushing both cylinders together and by using an elastomer ring, may be provided in the side wall of the upper cylinder. The two halves of the syringe must therefore be assembled with great precision, wherein there is a risk that if insufficient care is taken to prevent displacement of both cylinders with respect to one another, the vent will be re-exposed and the system will become unsealed and contaminated. Particularly complex measures must therefore be taken to prevent this.
Finally, EP 0 295 337 B1 describes a double chamber syringe for a solid and liquid pharmaceutical composition, wherein in the first lower chamber a toward the syringe head there is located a liquid substance which is separated via a double sided bypass and a stopper from a second upper chamber b in which a solution may be lyophilized, the wall of the chamber b having a small opening allowing the solvent to escape during the lyophilization. A drawback of this proposal is that there is a relatively small spacing between the opening and the lyophilizate solution. So, on application of vacuum, there is a risk that a portion of the solution will be extracted from the cylinder. The opening is therefore also correspondingly small, as a result of which, again, much less gas is able to escape per unit of time. A further problem is that after the lyophilization and sealing the solid is located at the top of the double chamber syringe and the liquid at the bottom (toward the mouth of the syringe), so the upper stopper is pressed onto, and will probably remain stuck to, the solid. After displacement of the stopper into the double bypass, the liquid in the lower chamber must be caused to move upward toward the solid in the upper chamber, and this is not easily possible. For this purpose, the syringe must, for example, be repeatedly rotated or shaken in order to rinse the solid out of the upper chamber and to convey it into the lower chamber where the port for the injection needle is located. The possibility of solid residues sticking to the upper stopper cannot be ruled out, so incomplete reconstitution takes place.
The above-described drawbacks demonstrate that there is still a need for a device which is easy to handle, for the reliable storage and mixing of two-component systems, of which one component is a lyophilizate and the other a solvent/dispersing medium therefor. It should, in particular, be possible to carry out lyophilization directly in the device, and this should reduce the drawbacks of the prior art. At the same time, contamination from outside should be prevented as far as possible. In particular, the subsequent mixing should take place without removing the components from the sterile interior of the device and without external intervention into the system resulting in loss of the sterile conditions. The device should also be easy to store. In addition, a process for the simple filling of such a device should be provided. The device and the process should also be suitable for implementation on an industrial scale.